Cannabis Sativa

Synthetic cannabinoids

Bag and contents of a well known early brand named Spice that contains herbs spiked with synthetic cannabinoids, now illegal throughout much of the world

Synthetic cannabinoids are a class of molecules that bind to cannabinoid receptors in the body (the same receptors to which THC and CBD attach, which are cannabinoids in cannabis plants). Synthetic cannabinoids are also designer drugs that are often sprayed onto plant matter.[1] They are typically consumed through smoking,[2] although more recently they have been consumed in a concentrated liquid form in the US and UK.[3] They have been marketed as herbal incense, or “herbal smoking blends”[2] and sold under common names like K2, Spice,[4] and Synthetic Marijuana.[1] They are also often labeled “not for human consumption.”[4]

When synthetic cannabinoid blends first went on sale in the early 2000s, it was thought that they achieved the psychoactive effects through a mixture of natural herbs. Laboratory analysis in 2008 showed that this was not the case, and that many in fact contained synthetic cannabinoids.[2] Today, synthetic cannabinoids are the most common new psychoactive substances to be reported. From 2008 to 2014, 142 synthetic cannabinoids were reported to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA).[5] A large and complex variety of synthetic cannabinoids are designed in an attempt to avoid the legal restrictions on cannabis, making synthetic cannabinoids designer drugs.[2]

In 2018 the United States Food and Drug Administration warned of significant health risks associated with synthetic cannabinoid products that contain the rat poison brodifacoum, which is added because it is thought to extend the duration of the drugs’ effects.[11] Severe illnesses and death have resulted from this contamination.[11]

Many of the early synthetic cannabinoids that were synthesized for use in research were named after either the scientist who first synthesized them or the institution or company where they originated. For example, JWH compounds are named after John W. Huffman and AM compounds are named after Alexandros Makriyannis, the scientists who first synthesized those cannabinoids. HU compounds are named after Hebrew University in Jerusalem, the institution where they were first synthesized, and CP compounds are named after Carl Pfizer, the company where they were first synthesized.

Use of the term “synthetic marijuana” to describe products containing synthetic cannabinoids is controversial and, according to Dr. Lewis Nelson, a medical toxicologist at the NYU School of Medicine, a misnomer. Nelson claims that relative to marijuana, products containing synthetic cannabinoids “are really quite different, and the effects are much more unpredictable. It’s dangerous.”[13] Since the term synthetic does not apply to the plant, but rather to the cannabinoid that the plant contains (THC), the term synthetic cannabinoid is more appropriate.[14]

Synthetic cannabinoids are known by a number of brand names including K2, Spice, Black Mamba, Bombay Blue, Genie, Zohai,[15] Banana Cream Nuke, Krypton, Lava Red, and many more.[16] In some Spanish-speaking countries, such as Chile and Argentina, such preparations are often referred to as “cripy.” They are often called “synthetic marijuana,” “natural herbs,” “herbal incense,” or “herbal smoking blends” and often labeled “not for human consumption.”[4] They are increasingly offered in e-cigarette form as “c-liquid”[17] with brand names such as Kronic.[18]

According to the Psychonaut Web Mapping Research Project, synthetic cannabinoids, sold under the brand name “Spice”, were first released in 2005 by the now-dormant company The Psyche Deli in London, UK. In 2006, the brand gained popularity. According to the Financial Times, the assets of The Psyche Deli rose from £65,000 in 2006 to £899,000 in 2007. The EMCDDA reported in 2009 that Spice products were identified in 21 of the 30 participating countries.[19]

Some early synthetic cannabinoids were also used in clinics. Nabilone, a first generation synthetic THC analog, has been used as an antiemetic, a drug to combat vomiting and nausea, since 1981. Synthetic THC (marinol, dronabinol) has been used as an antiemetic since 1985 and an appetite stimulant since 1991.[21]

In the early 2000s, synthetic cannabinoids started being used for recreational drug use in an attempt to get similar effects to cannabis. Since synthetic cannabinoids had different molecular structures to THC and other illegal cannabinoids, synthetic cannabinoids were technically legal, or at least not illegal, to sell or possess. Since the discovery of the use of synthetic cannabinoids for recreational use in 2008, some synthetic cannabinoids have been made illegal, but new analogs are continually synthesized that get around those restrictions. Synthetic cannabinoids have also been used recreationally because they are inexpensive and they are typically not identified by the standard marijuana drug tests. Unlike nabilone, the synthetic cannabinoids found being used for recreational use do not have any documented therapeutic effects.[16]

There are no fatal overdose cases linked to marijuana,[22] but deaths associated with synthetic cannabinoids are increasing.[23] The CDC found that the number of deaths from synthetic cannabinoid use tripled between 2014 and 2015.[10] These drugs are dangerous because they are more potent than marijuana, and due to the large quantity of different structures that fall under the same common names, users are often unaware of exactly what they are getting and how potent it is.[24] For example, Δ9-THC has an EC50 of 250 nM at CB1 and 1157 nM at CB2, whereas PB-22 has an EC50 of 5.1 nM at CB1 and 37 nM at CB2.[4]

No official studies have been conducted on the effects of synthetic cannabinoids on humans (as is often the case with illegal and potentially toxic compounds);[25] however, user reports and the effects experienced by patients seeking medical care after taking synthetic cannabinoids have been published. Each of the many different synthetic cannabinoids can have different effects, particularly different effects at different dosages. Some negative effects of 5F-PB-22 reported by users included nausea, vomiting, confusion, poor coordination, anxiety, and seizures. Some of the negative effects of 5F-AKB-48 reported by users included palpitations, paranoia, intense anxiety, and a taste like burned plastic.[5] The CDC recorded negative effects of synthetic cannabinoid overdose between 2010 and 2015 and of 277 drug overdose patients who reported synthetic cannabinoid as the sole agent, 66.1% reported problems in the central nervous system (e.g., agitation, coma, toxic psychosis), 17% reported cardiovascular problems (e.g., tachycardia, bradycardia), 7.6% reported pulmonary problems (5.4% of which had respiratory depression), and 4% reported acute kidney injury.[26]

Four postmortem cases linked to the synthetic cannabinoids 5F-PB-22 have been reviewed. The postmortem blood specimens contained a range of 1.1-1.5 ng/mL of 5F-PB-22. Three of the four cases were sudden episodes and the symptoms leading to death included acute shortness of breath; vasocongestion in the liver, spleen, and kidneys; bilateral pulmonary edema; dead inflamed tissue (necrotizing granulomatous inflammation); and congestion of most internal organs. The fourth case presented to the hospital with severe problems that deteriorated over the course of a day, ending with circulatory, respiratory, central nervous system, and renal failure.[29]

Studies are currently available that suggest an association between synthetic cannabinoids and psychosis.[30] The use of synthetic cannabinoids can be associated with psychosis and physicians are beginning to investigate if some patients with inexplicable psychotic symptoms may have at one point used synthetic cannabinoids. In contrast to most other recreational drugs, the dramatic psychotic state induced by use of synthetic cannabinoids has been reported, in multiple cases, to persist for several weeks, and in one case for seven months, after complete cessation of drug use.[31] Some studies suggest that not only can synthetic cannabinoids induce psychosis, but they can worsen previously stable psychotic disorders and might trigger a chronic (long-term) psychotic disorder among vulnerable individuals such as those with a family history of mental illness.[32] Individuals with risk factors for psychotic disorders are often counseled against using synthetic cannabinoids.[33] Psychiatrists have suggested that the lack of an antipsychotic chemical, like CBD in natural cannabis, may make synthetic cannabinoids more likely to induce psychosis than natural cannabis.[34]

There are five major categories for synthetic cannabinoids: classical cannabinoids, non-classical cannabinoids, hybrid cannabinoids, aminoalkylindoles, and eicosanoids. Classical cannabinoids are analogs of THC that are based on a dibenzopyran ring. They were developed starting in the 1960s, following the isolation of THC,[19] and were originally the only cannabinoids synthesized.[40] Classical cannabinoids include nabilone and dronabinol, and one of the best known synthetic classical cannabinoids is HU-210.[41]HU-210 is a chiral compound first synthesized by Raphael Mechoulam at Hebrew University in the 1980s. It was discovered in herbal incense products by the U.S. Customs and Border Protection in January 2009; however, classical cannabinoids are not often seen in synthetic cannabinoid blends for recreational use, likely because they are difficult to synthesize.[42]

Non-classical cannabinoids include cyclohexylphenols (CP), which were first synthesized in the late 1970s to 1980s by Pfizer as potential analgesics.[41] The C8 homologue of CP-47,497 (CP-47,497-C8) was one of the first synthetic cannabinoids being used recreationally. CP-47,497-C8 is made by extending the dimethylheptyl side chain of CP-47,497 to a dimethyloctyl side chain. It was discovered by forensic scientists in an herbal blend known as “Spice” in 2008, along with JWH-018, an aminoalkylindole.[4]

Hybrid cannabinoids have a combination of classical and non-classical cannabinoid structural features.[40] For example, AM-4030, a derivative of HU-210, is a hybrid cannabinoid because it has the dibenzopyran ring common of classical cannabinoids and an aliphatic hydroxyl group common in the CP family of nonclassical cannabinoids.[43]

The synthetic cannabinoids that have emerged recently have even greater structural diversity, possibly to subvert legal regulations on earlier generations of synthetic cannabinoids. There are a few different structural classifications of synthetic cannabinoids that include many of the new structures, some of which are shown in Table 1. The indazole carboxamide group, including APINACA (AKB-48), an adamantyl indazole carboxamide, and AB-PINACA, an aminocarbonyl indazole carboxamide, is an example of a new group of synthetic cannabinoids.[41] Most clandestine manufacturers and producers only make small changes to the structure of a synthetic cannabinoid, such as changing an indole to indazole structure (AM-2201 to THJ-2201) or terminal fluorine replacement;[3] however, one group that was unprecedented when discovered by forensic scientists in 2013, was the quinolinyl ester synthetic cannabinoids.[4]

PB-22 and 5F-PB-22 were the first synthetic cannabinoids to include a quinoline substructure and an ester linkage. These compounds are thought to have been synthesized with the intention of making a synthetic cannabinoid prodrug, which might improve absorption and confound detection. Ester bonds are easily biodegradable through spontaneous or endogenous, nonspecific esterase hydrolysis, which has been commonly used in medicinal chemistry to make ester prodrugs. The reason for the change to the quinolone substructure is unknown, but it may have been found to be a suitable replacement for the naphthoyl moiety that is currently regulated by US scheduling laws.[39]

Although most synthetic cannabinoids are not direct analogs of THC, they share many common features with THC. Most are lipid-soluble, non-polar, small molecules (usually 20-26 carbon atoms) that are fairly volatile, making them “smokable,” like THC.[19] Another common feature of most synthetic cannabinoids and THC is a side-chain of 5-9 saturated carbon atoms. It has been found that this chain of 5-9 carbons is required for optimal psychotropic activity from binding CB1 receptors.[16] Also, most synthetic cannabinoids are agonists of both cannabinoid receptors, CB1 and CB2, like THC; however, they often have greater binding affinity and therefore greater potency than THC, as seen in Table 2. Due to the greater potency, the standard doses of many synthetic cannabinoids may be less than 1 mg.[19]

Table 2. Structure, Binding Affinity, and Potency of Popular Synthetic Cannabinoids and THC

Recently there has been an increase in the emergence of terminally fluorinated synthetic cannabinoids, such as 5F-PB-22 (fluorinated version of PB-22) and XLR-11 (fluorinated version of UR-144). South Korea’s National Forensic Service reported that 90% of all seized synthetic cannabinoids in 2013 were fluorinated, compared to no fluorinated synthetic cannabinoids reported in 2010. 5F-derivations (terminal fluorination) of the synthetic cannabinoids have been found to be about 2-5 times more potent at CB1 receptors than their un-fluorinated counterparts,[4] as shown in Table 2.

Synthetic cannabinoids are typically not identified by the standard marijuana drug tests including the immunoassay test (EMIT), GC-MS screening, and multi-target screening by LC-GC/MS because those tests only detect the presence of THC and its metabolites.[50][51] Although most synthetic cannabinoids are analogs of THC, they are structurally different enough that, for example, the specific antibodies in the EMIT for marijuana do not bind to them.[52] Also, due to their high potency, a very small dose of synthetic cannabinoids is used; moreover, synthetic cannabinoids are highly metabolized by the body, so the window to detect the parent drug (the synthetic cannabinoid itself) in blood and oral fluid is very small.[53]

Serum concentrations of synthetic cannabinoids are generally in the 1–10 μg/L range during the first few hours after recreational usage and the metabolites are usually present in urine at similar concentrations.[54] Little to no parent drug is present in urine, so there is a lot of research to try and identify the major urinary metabolites that could be used as markers of synthetic cannabinoid intake.[3] The major urinary metabolites in most cases are formed by oxidation of the alkyl side-chain to an alcohol and carboxylic acid followed by glucuronide conjugation and also by N-dealkylation and aromatic hydroxylation.[55] For example, the main metabolites of JWH-018, of which there are over 20, include carboxylated, monohydroxylated, dihydroxylated, and trihydroxylated metabolites, but they are mostly excreted in urine as glucuronide conjugates.[42] The presence of synthetic cannabinoids or their metabolites in bodily fluids may be determined using specifically-targeted commercially available immunoassay screening methods (EMIT), while liquid chromatography-mass spectrometry is most often used for confirmation and quantitation.[56][57][58] There are commercially available EMIT kits for the screening of the synthetic cannabinoids JWH-018, JWH-073, JWH-398, JWH-200, JWH-019, JWH-122, JWH-081, JWH-250, JWH-203, CP-47,497, CP-47,497-C8, HU-210, HU-211, AM-2201, AM-694, RCS-4, and RCS-8 through companies like NMS Labs, Cayman Chemical, and Immunoanalysis Corporation.[59]

In the autumn of 2014, more than two-thousand Spice consumers in Russia sought medical attention, one-thousand were admitted to hospitals, and 40 people died.[61]

On July 12, 2016, 33 people were intoxicated by an herbal “incense” product called “AK-47 24 Karat Gold,”[62] and dozens overdosed, in Brooklyn. 18 people were transported to local hospitals.[63] This mass intoxication event was referred to as a “zombie” outbreak in the press due to the description of the intoxicated persons by bystanders as “zombielike” (moved slowly, had blank stares, and occasionally groaned).[64] The herbal “incense” product was determined to be a synthetic cannabinoid called AMB-FUBINACA.[62]

Since March 2018, Illinois, Wisconsin, Maryland, and 8 other states in the United States have had an outbreak of severe bleeding caused by a synthetic cannabinoid contaminated with brodifacoum, a rat poison that causes bleeding. Illinois was hit the hardest[65] and on April 5, 2018, the CDC issued a Clinical Action alert to health care providers across the United States advising of 89 confirmed cases of “serious unexplained bleeding” in Illinois. The cases are still being studied; however, 63 of the patients reported synthetic cannabinoid use, and laboratory analysis confirmed brodifacoum was present in at least 18 patients.[66] As of April 24, 2018, 153 cases, including four deaths, linked to this outbreak have been reported to the Illinois Department of Public Health (IDPH) since March 7, 2018.[67] On September 18, 2018, the Wisconsin Department of Health Services confirmed 16 more cases, bringing the total number of people affected by the outbreak in Wisconsin to 80 people since March 2018, including one death in July 2018.[68]

In August 2018, there were almost one hundred overdose cases reported over two days in New Haven, Connecticut from a bad batch of K2. The synthetic cannabinoid was believed to have been mixed with fentanyl, although no fentanyl was identified in samples of the drug tested by the DEA.[69]

From September 21-22, 2018, almost 50 people overdosed and two people died in the Kensington area of Philadelphia. Tests are still in progress, but officials believe the cause to be a combination of heroin or fentanyl and a synthetic cannabinoid.[71] This same area in Philadelphia had 155 people overdose and 10 people die from a combination of heroin, fentanyl, and a synthetic cannabinoid called 5F-ADB over one weekend in July 2018. The Department of Public Health released that they believe “5F-ADB was the primary cause of the cluster of patients with these adverse drug reactions.”[72]

The Austrian Ministry of Health announced on December 18, 2008 that Spice would be controlled under Paragraph 78 of their drug law on the grounds that it contains an active substance that affects the functions of the body, and the legality of JWH-018 is under review.[73][74][75]

JWH-018, CP 47,497 and the C6, C8 and C9 homologues of CP 47,497 have been illegal in Germany since January 22, 2009.[76][77] Since November 26, 2016 about 80-90% of the substances belonging to the group of synthetic cannabinoids are illegal in Germany.(Since the NpS-Law doesn’t cover all chemical structures) [78]

JWH-018, JWH-073, CP 47,497 (and its homologues), and HU-210 as well as leonotis leonurus have been all banned in Latvia since 2005.[81] After the first confirmed lethal case from the use of legal drugs in late 2013, parliament significantly increased the number of temporarily banned substances used in Spice and similar preparations. On April 3, 2014, parliament made selling of the temporarily banned substances a criminal offense.[82]

On April 9, 2009, the Chief Medical Officer of the Russian Federation issued a resolution on reinforcing control over the sales of smoking blends. These blends, marketed under the trade names AM-HI-CO, Dream, Spice (Gold, Diamond), Zoom, Ex-ses, Yucatán Fire and others, have been declared to contain Salvia divinorum, Hawaiian wood rose, and blue lotus, and are prohibited to be sold. These substances have been found to have “psychotropic, narcotic effects, contain poisonous components and represent potential threat for humans”. The resolution does not mention JWH-018 or other synthetic cannabinoids.[88] On January 14, 2010, the Russian government issued a statement including 23 synthetic cannabinoids found in smoking blends Hawaiian Rose and Blue Lotus on the list of prohibited narcotic and psychotropic substances.[89]

About 780 new psychoactive substances were added to the list from 2011 to 2014. The drugmakers avoided all the bans by making slight changes to the drugs. In the autumn of 2014, more than two-thousand Spice consumers in Russia sought medical attention, one-thousand were admitted to hospitals, and 40 people died[61] On October 30, 2014, President Vladimir Putin brought in a bill that increased the penalty for selling or consuming smoking blends from a fine to up to eight years in prison.[90]

Spice is legal in Slovakia. The National Anti-Drug Unit is considering adding it to the list of controlled substances.[91] The latest anti-drug law version (468/2009) valid since January 2010 does not mention active compounds of Spice.[92]

Spice is unregulated in Spain. For this reason, Spice is available in grow shop stores or cannabis related stores, and it can be bought and shipped online without any legal impediment from those kind of stores.[93] However, as Spanish law permits growing up to two cannabis plants per household, and the possession and consumption of cannabis on private property is also legal, cannabis alternatives like Spice are largely redundant and thus remain relatively unknown in Spain.[94]

CP 47,497-C6, CP 47,497-C7, CP 47,497-C8, CP 47,497-C9, JWH-018, JWH-073 and HU-210 were all made illegal in Sweden on September 15, 2009. The bill was accepted on July 30, 2009 and was put in effect on September 15, 2009.[95]

Spice, which is colloquially called bonzai in Turkey, was added to the list of drugs and psychotropic substances on July 1, 2011 by the law numbered as 2011/1310 B.K.K. (February 13, 2011 and the Official Gazette No. 27845).[97]

Many cannabinoids were legal in the United Kingdom until December 2009, when they were classified as Class B drugs.[98] The UK continued to ban new synthetic cannabinoids as they came to market but they were typically replaced instantly by novel alternatives. In May 2016, the Psychoactive Substances Act[99] came into force, which intends to restrict the production, sale and supply of new psychoactive substances.

Spice is not specifically prohibited in Canada, but synthetic cannabis mimics are listed as a schedule II drug. Schedule II to the Controlled Drugs and Substances Act makes reference to specific synthetic compounds JWH-XXX and AM-XXXX, although is not limiting to those identified.[100][101]Health Canada is debating the subject.[102][103]

The case of David Mitchell Rozga, an American teenager from Indianola, Iowa, brought international attention to K2. Rozga shot himself in the head with a family-owned hunting rifle in an apparent suicide on June 6, 2010. After news of Rozga’s death, it was reported by friends that they had smoked K2 with Rozga approximately one hour before his death. The nature of his death and reports from numerous family members, had led investigators to suspect that it was likely Rozga was under the influence of a mind-altering substance, at the time of his death. The death of Rozga has been used as a face of political lobbying against the continuation of K2, and other legal synthetic drugs, such as bath salts.
Following the incident, an act to ban the use and distribution of the drug was proposed by US Senator Chuck Grassley of Iowa as the “David Mitchell Rozga Act”. It was approved into legislation by the United States Congress in June 2011.[104] On July 10, 2012, President Barack Obama signed the Synthetic Drug Abuse Prevention Act of 2012 into law. It banned synthetic compounds commonly found in synthetic marijuana, placing them under Schedule I of the Controlled Substances Act.[105]

Prior to that, some compounds within synthetic cannabis mimics (HU-210) were scheduled in the US under federal law, while others (JWH-073) have been temporarily scheduled until final determination of their status can be made.[106][107][108][109] The Drug Enforcement Administration (DEA) considers it to be a “drug of concern”,[110] citing “…a surge in emergency-room visits and calls to poison-control centers. Adverse health effects associated with its use include seizures, hallucinations, paranoid behavior, agitation, anxiety, nausea, vomiting, racing heartbeat, and elevated blood pressure.”[111][112]

Several states independently passed acts making it illegal under state law, including Kansas in March 2010,[113]Georgia and Alabama in May 2010,[114][115]Tennessee and Missouri in July 2010,[116][117]Louisiana in August 2010,[citation needed]Mississippi in September 2010,[citation needed] and Iowa.[118] An emergency order was passed in Arkansas in July 2010 banning the sale of synthetic cannabis mimics.[119] In October 2010, the Oregon Board of Pharmacy listed synthetic cannabinoid chemicals on its Schedule 1 of controlled substance, which means that the sale and possession of these substances is illegal under the Oregon Uniform Controlled Substances Act.[120] According to the National Conference of State Legislatures, several other states are also considering legislation, including New Jersey, New York, Florida, and Ohio.[117] Illinois passed a law on July 27, 2010 banning all synthetic cannabinoids that goes into effect January 1, 2011.[121] Michigan banned synthetic cannabinoids in October 2010,[122] and the South DakotaLegislature passed a ban on these products which was signed into law by Gov. Dennis Daugaard on February 23, 2012 (and which took immediate effect under an emergency clause of the state constitution).[123]Indiana banned synthetic cannabinoids in a law which became effective in March 2012.[124]North Carolina banned synthetic cannabis mimics by a unanimous vote of the state senate, due to concerns that its contents and effects are reasonably similar to cannabis, and may cause equal effects in terms of psychological dependency.[125][126]

Following cases in Japan involving the use of synthetic cannabinoids by navy, army and marine corps personnel resulted in the official banning of it,[127] a punitive general order issued on January 4, 2010 by the Commander Marine Corps Forces, Pacific prohibits the actual or attempted possession, use, sale, distribution and manufacture of synthetic cannabis mimics as well as any derivative, analogue or variant of it.[128] On June 8, 2010, the US Air Force issued a memorandum that banned the possession and use of Spice, or any other mood-altering substance except alcohol or tobacco, among its service members.[129]

On November 24, 2010, the DEA announced that it would make JWH-018, JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol, which are often found in synthetic cannabis mimics, illegal using emergency powers.[130] They will be placed in Schedule I of the Controlled Substances Act, within a month of the announcement, and the ban will last for at least a year.[131][132] The temporary ban, for at least a year, came into effect on March 1, 2011.[133]

On June 17, 2011, the Western Australian government banned all of the synthetic cannabinoids found in already existing products, including brands such as Kronic, Kalma, Voodoo, Kaos, and Mango Kush. Western Australia was the first state in Australia to prohibit the sale of certain synthetic cannabinoids.[137][18] On June 18, 2013, an interim ban made a large list of product brands and synthetic substances illegal to sell anywhere in Australia.[138] This ban lapsed on October 13, 2013, and a permanent ban has not been imposed.[139] Synthetic cannabinoids and related products remain illegal in NSW, where a bill was passed on September 18, 2013, that bans entire families of synthetic drugs instead of only banning existing compounds that have been identified.[140][141] The introduction of this law makes NSW the first state in Australia to completely ban substances with psychoactive properties.[141]

Spice is illegal in New Zealand, it is classified as a Class C controlled drug.[142] The New Zealand Parliament passed a law in July 2013 banning the sale of legal highs in dairies and supermarkets, but allowing some “low risk” drugs to continue to be sold through speciality licensed shops.[143] Synthetic cannabinoids, as well as all other legal highs were outlawed at midnight on 7 May 2014, after a law was passed a week prior by the New Zealand government.[144]

^Iowa Code § 124.204(4)(u)(PDF) (defining a Schedule I controlled substance to include “synthetic equivalents of the substances contained in the cannabis plant, or in the resinous extractives of such plant, and synthetic substances, derivatives, and their isomers with similar chemical structure and pharmacological activity to those substances contained in the plant….”)